Figure 1.

The KEAP1-NFE2L2 signaling pathway. NFE2L2 is primarily regulated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, which, under normal conditions, promotes the ubiquitination and proteasomal degradation of NFE2L2, keeping its cellular levels low. However, in response to oxidative stress or electrophilic agents, key cysteine residues on KEAP1 are modified, preventing NFE2L2 ubiquitination. As a result, NFE2L2 stabilizes and accumulates in the cytoplasm before translocating to the nucleus. There, it dimerizes with sMAF proteins and binds to AREs in the promoters of target genes. These genes regulate a variety of crucial cellular processes, including antioxidant defense, detoxification, cell proliferation and death, autophagy, metabolism, mitochondrial function, and iron homeostasis. Through these pathways, NFE2L2-mediated gene expression plays an essential role in protecting cells from oxidative damage, maintaining redox balance, and ensuring overall cellular homeostasis. KEAP1: Kelch-like ECH-associated protein 1; NFE2L2: NFE2-like basic leucine zipper transcription factor 2; CUL3: cullin 3; RBX1: ring-box 1; sMAF: small musculoaponeurotic fibrosarcoma; AREs: antioxidant response elements.